Controlled drug delivery devices offer clinically significant advantages for various therapeutically active agents by way of increasing patient compliance due to reduced frequency of administration, improve the safety and efficacy of drug substances and reduce undesirable effects in comparison to the corresponding immediate release dosage form. The advantages of controlled release or sustained release or modified release products are well known in the pharmaceutical field.
Many such drug delivery devices are commercially available and are produced by various technologies known in the art. However, some of these technologies require special processes and equipment for production. In addition, some of these systems have limited applications because their ability to produce a desired release profile of a therapeutic agent depends upon several factors, e.g., the physico-chemical properties of therapeutic agent, additives in the drug delivery device, physiological factors and the like. The object of a controlled drug delivery device or composition is to limit, control or modify (e.g., slow) the drug release characteristics relative to an immediate release system of the same drug. While, many controlled release formulations are already known, certain moderately to poorly soluble or practically insoluble drugs present formulation difficulties and cannot be successfully formulated as a controlled drug delivery device employing these formulation techniques. In addition, due to variability in physico-chemical characteristics of the therapeutic agent, variation in their response in the body upon administration and variation in their response on combining with additives, some of the existing technologies are inadequate. The emergence of newer therapeutic agents and understanding of pharmacokinetics and physiological needs make the task of controlled drug delivery more complex.
Clarithromycin is a 14-membered macrolide antimicrobial agent that exhibits a broad spectrum of antimicrobial activity against gram-positive and gram-negative pathogens making it suitable for numerous clinical situations demanding antibacterial agents. Depending on the pharmacokinetic characteristics, antibacterial agents may be administered orally more than once per day to maintain a minimum effective concentration throughout the day and night. However, a more desirable dosage regimen is once a day administration. Currently, Clarithromycin is administered twice daily in the form of commercially available immediate release compositions. Clarithromycin is practically insoluble in water and shows pH dependent solubility profile. The solubility significantly increases at lower pH values (I. I. Salem, Analytical Profiles of Drug Substances and Excipients, Volume 24, Academic Press, (1996) at 46–85)
Clarithromycin undergoes degradation in acidic medium. It degrades rapidly at normal gastric pH of 1.0–2.0 (P. O. Erah et. al., J. Antimicrob. Chemother. 39, 5–12, (1997)). On the market, Clarithromycin is present in the form of film coated tablets, a suspension and extended-release tablets.
Various compositions with extended-release characteristics are known in the art for example, Horder et al. (U.S. Pat. No. 4,842,866), disclose a slow release composition comprising sodium alginate, sodium-calcium alginate and a therapeutically effective ingredient.
Broad et al. (U.S. Pat. No. 5,705,190) disclose a controlled release solid pharmaceutical compositions adopted for oral administration comprising a water soluble alginate salt, a complex salt of alginic acid, wherein the cation is selected from the group consisting of calcium, strontium, iron or barium, and an organic carboxylic acid to facilitate dissolution of basic drug. These formulations are said to be suitable for once a day administration. The release rate of the Clarithromycin is controlled using a matrix based on a water-soluble alginate salt and a complex salt of alginic acid.
The release model of a drug from calcium alginate matrices has been shown to be highly dependent on the release medium. Cross-linking calcium ions were rapidly discharged from the matrices in the presence of acid and affected the ability to provide delayed drug release. (Ostberg, T. et. al., Int. J. Pharm. 112, 241–248 (1994)). It appears that such interactions may lead to inconsistent and unpredictable drug release upon administration of alginate based controlled drug delivery devices.
Al-Razzak et al. (U.S. Pat. No. 6,010,718) disclose a pharmaceutical composition for extended release of an erythromycin derivative in a gastrointestinal environment. The composition includes an erythromycin derivative and a hydrophilic water-soluble polymer. The polymer is selected from group consisting of polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (HPMC), methyl cellulose, vinyl acetate/crotonic acid copolymers, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures.
Compositions based on hydrophilic water-soluble polymers commonly exhibit an initial “burst effect” which causes a non-linear release rate of a drug. (See, e.g., U.S. Pat. No. 5,419,917.) Polymers such as hydroxypropylmethyl cellulose can be hydrated at low pH levels to form a viscous gel layer that controls drug release. During drug release, at high pH levels, however the tablets become smaller and smaller due to polymer erosion. The size reduction leads to a reduction in the surface area that may affect the dissolution rate. (See U.S. Pat. No. 5,695,781.)
The processing of these hydrophilic water-soluble polymers such as hydroxypropylmethyl cellulose, is difficult and requires strict controls. For example, Koji et al. (JP 09095440) disclose a lyophilized composition of a fluid mixture of medicine and hydrogel forming polymer (such as hydroxypropyl cellulose, and hydroxypropylmethyl cellulose). The Koji composition is said to float in the stomach and release a medicament slowly.
Gel forming cellulose ethers (e.g., hydroxypropyl cellulose and hydroxypropylmethyl cellulose) have been used in controlled release of drug delivery to preparing matrix systems. However, the mechanism of release from these matrices depends on the aqueous solubility of the drug and the hydrophilicity of the polymer used. (A. G. Thombre & J. R. Cardinal in Encyclopedia of Pharmaceutical Technology, Volume 2, 1990, 61–88).
Lek (WO 00/48607) discloses a formulation including Clarithromycin or a derivative and a mixture of fatty and hydrophilic components. The formulation also includes a surfactant and pH modulator, along with other pharmaceutically acceptable additives. An acid resistant coating on the tablet formulation has been disclosed.
Insoluble polymers such as ethyl cellulose (EC) have been used for controlling the release of therapeutic agents from drug delivery devices. For example, ethyl cellulose has been used extensively as a coating layer for dosage forms to control the release of a therapeutic agent. However, ethyl cellulose is insoluble at gastrointestinal pH. Therefore, the drug release depends upon the permeability of the EC films. The aqueous fluids penetrate and dissolve the drug, which can diffuse out from the dosage form. The rate of release is dependent upon the drug solubility in the gastrointestinal environment. Thus, the coatings may provide a formulation having a pH dependent release rate and variability in the release rate of drugs that are insoluble at gastrointestinal pH. Moreover, the coating process requires a controlled operation because a variation in the thickness of the coating on the composition can lead to variation in drug release.
Attempts have been made to incorporate ethyl cellulose in sustained release matrix. Radebaugh et al. (U.S. Pat. No. 5,462,747) disclose a process for preparing a composition of a pharmaceutically active agent for sustained release, in the form of shaped tablets or tablet layers, characterized by a long lasting slow and relatively regular incremental release of a the active agent upon administration. The composition includes a granulating agent such as povidone, a polymer such as ethyl cellulose, a wicking agent such as microcrystalline cellulose, erosion promoter such as pregelatinized starch to form a granulation. The granulation is then blended with a composition of an active agent an erosion promoter, wicking agent, lubricant, glidant before compressing into tablet. The goal of the '747 patent is said to be a long lasting and relatively regular incremental release of the pharmaceutically active agent upon administration. The release has been shown to be pH independent. The amount of EC is from 3–12 parts by weight of total non-active components of tablet. The pharmaceutically active agent is selected from various therapeutic categories.
Eichel et al. (U.S. Pat. No. 5,478,573) describe a delayed, sustained-release pharmaceutical preparation including a core of a drug such as propranolol hydrochloride surrounded by a hydrated diffusion barrier having thickness of at least 20 microns, comprising of film forming polymer mixture of an acrylic resin and ethyl cellulose. In one embodiment an acrylic resin such as Eudragit RS 30D and RL 30D are mentioned. The core drug is preferably a water-soluble drug. The thickness of the barrier layer is such that less than 5% of drug dissolves within 2 hours of administration.
Clarithromycin is very soluble in the stomach and fairly soluble in the upper region of small intestine where absorption is most likely to occur. As the drug's solubility decreases in the lower intestine, less drug is available for absorption. (See, e.g., U.S. Pat. No. 5,705,190.) Usually the time required for such type of composition to pass through distal end of small intestine is 6 to 8 hrs.
Thus, a continuing need exists for compositions capable of delivering therapeutic agents, such as, for example, Clarithromycin in at a rate sufficient to provide a beneficial effect, wherein the maximum delivery of the therapeutic agent will be within the 6–8 hour absorption window.
There is a need for a controlled drug delivery devices, such as, tablets, caplets, capsules, and the like, for delivery of therapeutic agents, which are capable of offering the advantages associated with a controlled drug delivery device while maintaining the desired bioavailability after administration.
In one aspect the invention provides a controlled release pharmaceutical compositions for an acid labile, poorly soluble therapeutic agent, exhibiting pH dependent solubility characteristics when exposed to aqueous environment.
In another aspect the present invention provides a controlled release composition and simple method for preparing a controlled release composition for macrolide antibacterial agents such as, for example, Clarithromycin salts and derivatives thereof.
In another aspect the present invention provides a convenient dosage form for Clarithromycin, a pharmaceutical salt or a derivative thereof that facilitates patient compliance.
Yet another aspect the present invention provides a process for making a controlled release compressed dosage form such as tablet, pill, or caplet of a therapeutic agent when present in a physical form is difficult to compress or has poor flow or results in said dosage forms having poor physical characteristics like friability or defects like capping or lamination which otherwise requires special equipments or excipients to produce said dosage forms. The therapeutic agent is selected from group comprising of macrolide group of antibacterial agents such as clarithromycin.